The overall goal of this Program is to improve the survival of cancer patients by active specific immunotherapy. To achieve this goal, we will utilize melanoma as a model neoplasm. This renewal application represents a continuation of our previous studies with polyvalent melanoma cell vaccine (PMCV) and investigates the in vivo and in vitro mechanisms of PMCV anticancer activity. The first project is a new project for this renewal which will build on the past successes of this program by utilizing both adoptive and active immunotherapy and targeted vaccine designs to induce antigen specific immune responses. Patients? dendritic cells will be fused with the autologous tumor cells present in the PMCV by electrofusion. Phase I/II clinical trials will be conducted. The second project will continue to utilize already established, as well as developing new, molecular assays using both RNA and DNA markers present in blood and tumors as surrogates to predict disease progression, outcome and treatment efficacy. The third project will complete a randomized Phase III trial in AJCC stage III melanoma to compare PMCV plus BCG compared to BCG alone measuring disease free and overall survival after surgery. This project will also develop an immunological response model for predicting outcomes following vaccine therapy, undertake studies utilizing cytokines to improve vaccine immunotherapy and develop new tumor markers to detect subclinical metastatic disease. All projects rely upon the support of four cores: Administrative and Clinical Support Services, Biostatistics, Serum, Lymphocyte and Tissue Collection, and Molecular Support.